Compostitions for increasing energy in vivo

ABSTRACT

Precursors of adenosine triphosphate are administered orally to increase intracellular ATP concentration as dietary supplements or for treatment of reduced energy availability resulting from strenuous physical activity, illness or trauma. Pentose sugars are administered individually, mixed into dry food or in solution. The preferred pentose is D-ribose, singly or combined with creatine, pyruvate, L-carnitine and/or vasodilating agents. Additionally, magnesium, electrolytes, fatty acids and hexose sugars can be used. The compositions and methods of this invention are especially beneficial to mammals having reduced energy availability or high energy demand.

FIELD OF THE INVENTION

[0001] The present invention relates to compositions and methods forincreasing the energy available to mammals having reduced energyavailability or expending high levels of energy. Such mammals includehumans with illnesses resulting in reduced intracellular adenosinetriphosphate (ATP), humans engaged in heavy physical activity such asathletes or laborers, and humans desiring to increase their energylevels. Other mammals such as dogs and cats are also included in thepresent method. Administration of the compositions of the inventionprovides increased levels of blood and intracellular ATP, extends thetime and intensity at which a mammal can exercise, and increases therate of oxygen utilization by the exercising subject. Non-exercisingmammals and those that expend a higher than normal level of energyduring recovery from physical insults such as trauma, burns and sepsisalso benefit from administration of the compositions of the invention.

BACKGROUND OF THE INVENTION

[0002] It is well known that the energy coinage of the cell is adenosinetriphosphate (ATP). During anabolism, the energy derived from themetabolism of nutrients is transferred to high energy phosphate bonds ofATP. The energy in these bonds is expended during the energy consumptionphase. An important and “costly” expenditure, in which ATP is rapidlycycled, is that required for muscular contraction.

[0003] The energy buildup steps occur within the muscle cell during twobasic processes. Oxidative phosphorylation replenishes ATP by thebreakdown of circulating fatty acids, glucose and intramuscular glycogenand triglycerides. Anaerobic phosphorylation provides ATP from creatinephosphate, circulating glucose and intramuscular glycogen via kinasereactions such as the myokinase reaction.

[0004] U.S. Pat. No. 5,714,515 describes the administration ofcompositions containing pyruvate, an intermediate breakdown product ofglucose, to enhance recovery from surgical or accidental trauma, shock,exhaustion due to prolonged physical effort and other indications. U.S.Pat. No. 5,709,971 discloses the administration of other glucosemetabolites, namely glyceraldehyde-3-phosphate, phosphoenolpyruvate and3-phosphoglycerate, in combination with nicotineadeninedinucleotide,coenzyme A and acetyl coenzyme A.

[0005] A different approach to increasing the substrates available forproduction of ATP that has been employed is the administration of theamino acid L-carnitine, which is thought to enhance the transport andabsorption of fatty acids into mitochondria, the site of oxidativephosphorylation. U.S. Pat. No. 4,968,719 describes the use ofL-carnitine for the treatment of peripheral vascular diseases.

[0006] Regardless of whether the high energy phosphate bonds of ATP aregenerated oxidatively or anaerobically, and irrespective of thesubstrates used for its generation, ATP cannot be synthesized unless theprecursors of the ATP molecule itself are available. The resynthesis ofthe ATP molecule can occur by de novo or salvage pathways.

[0007] In the synthesis of ATP via the nucleotide salvage pathway, thenucleotide precursors that may be present in the tissue are converted toAMP and further phosphorylated to ATP. Adenosine is directlyphosphorylated to AMP, while xanthine and inosine are first ribosylatedby 5-phosphoribosyl-1-pyrophosphate (PRPP) and then converted to AMP.Ribose is found in the normal diet only in very low amounts, and issynthesized within the body by the pentose phosphate pathway. In the denovo synthetic pathway, ribose is phosphorylated to PRPP, and condensedwith adenine to form the intermediate adenosine monophosphate (AMP.) AMPis further phosphorylated via high energy bonds to form adenosinediphosphate (ADP) and ATP.

[0008] Synthesis by the de novo pathway is slow. Normally, AMP synthesisis believed to occur mainly by the salvage pathway, however, followinganoxia or ischemia, the activity of the de novo pathway is increased.

[0009] During energy consumption, ATP loses one high energy bond to formADP, which can be hydrolyzed to AMP. AMP and its metabolites adenine,hypoxanthine and inosine are freely diffusible from the muscle cell andmay not be available for resynthesis to ATP via the salvage pathway.

[0010] In U.S. Pat. No. 4,719,201, it is disclosed that when ATP ishydrolyzed to AMP in cardiac muscle during ischemia, the AMP is furthermetabolized to adenosine, inosine and hypoxanthine, which are lost fromthe cell upon reperfusion. In the absence of AMP, rephosphorylation toADP and ATP cannot take place. Since the precursors were washed from thecell, the nucleotide salvage pathway is not available to replenish ATPlevels. It is disclosed that when ribose is administered via intravenousperfusion into a heart recovering from ischemia, recovery of ATP levelsis enhanced.

[0011] Pliml, in German Patent No. 4,228,215, found that oral ribose waseffective in treating cardiac insufficiency and hypovolemic shock inhumans.

[0012] The advantage of the administration of pentoses such as ribose orxylitol to prevent pain and stiffness of skeletal muscle in patientssuffering from the autosomal recessive genetic disease myoadenylatedeaminase (MAD) deficiency was shown by Zöllner et al. (KlinischeWochenshritt 64:1281-1290, 1986.) This disease is characterized bypermanent muscular hypotonia, excessive muscular weakness, fatigue,soreness, burning pain, stiffness and cramps. These symptoms areconsidered to be consequences of the interruption of the ATP cycle.Dephosphorylation of ATP is inhibited by the accumulation of AMP,resulting in less available energy to effect muscle contraction andrelaxation. However, even though symptoms of MAD-deficient patients wererelieved by administration of ribose, the intracellular levels ofadenine nucleotides remained abnormally high and normal volunteersexperienced no beneficial effect from ribose administration. (Gross,Reiter and Zöllner, Klinische Wochenshritt, 67:1205-1213, 1989.)

[0013] Tullson et al. (Am. J. Physiol., 261 (Cell Physiol. 30) C343-347,1991) cite references showing that high intensity exercise increasesdegradation and subsequent loss of AMP from isolated muscle. Theyfurther disclose that adding ribose to the perfusate in a rathindquarter preparation increases the de novo synthesis of AMP insedentary muscle, but does not eliminate the decline in de novosynthesis seen in contracting muscle.

[0014] Carniglia, et al, U.S. Pat. No. 4,871,718, disclose that when acomplex mixture comprising amino acids, metabolites, electrolytes andribose or a precursor of ribose, was administered orally as a dietarysupplement to race horses, increases in intracellular ATP levels andphysical performance result. The performance evaluation was anecdotal,however, based on the subject's performance history.

[0015] Thus, a continuing need exists for simple methods to enhanceskeletal muscle performance in normal mammals; that is, mammals that arenot at the time of application of the method experiencing ischemia,prior to or undergoing physical activity. A need also exists for amethod to increase the energy level of mammals to provide an increasedfeeling of well-being.

SUMMARY OF THE INVENTION

[0016] The present invention provides compositions and methods ofincreasing the energy level in a mammal. It is believed that the presentcompositions and methods function by stimulating the synthesis of ATP ina mammal experiencing a less than optimal availability of ATP in orderto support cellular function. Specifically, a pentose such as D-riboseis given orally before, during and after a period of high ATP demand, inamounts effective to enhance the energy of the mammal. Mammals givenribose are able to exercise longer, to achieve a higher intensity andsubjectively have more energy than those not given ribose.

[0017] It is proposed that the cellular concentration of PRPP is thelimiting factor in recovery or increase of ATP levels via either the denovo or nucleotide salvage pathways and that the administration ofribose can stimulate ATP synthesis, providing larger pools of ATP forenergy expenditure. Mammals experiencing a less than optimalavailability of ATP include normal, healthy subjects undergoing highenergy demand such as athletes, and workers performing heavy labor. Itis further proposed that normal subjects even in the resting state willexperience a positive feeling of enhanced well-being afteradministration of effective amounts of ribose.

[0018] The availability of PRPP appears to control the activity of boththe salvage and de novo pathways, as well as the direct conversion ofadenine to ATP. Production of PRPP from glucose appears to be limited bythe enzyme glucose-6-phosphate dehydrogenase (G6PDH). Glucose isconverted by enzymes such as G6PDH to ribose-5-phosphate and furtherphosphorylated to PRPP, which augments the de novo and salvage pathways,as well as the utilization of adenine. The addition of ribose bypassesthis rate limiting enzymatic step.

[0019] Also included in the group of subjects benefiting from the methodof the invention are mammals having a chronic low energy level due toadvanced age, trauma, sepsis, or such disease conditions as congestiveheart failure and other chronic illnesses.

[0020] Compositions that enhance the pentose benefit are also provided.Such compositions preferably comprise at least one ofmagnesium,-creatine, pyruvate, L-carnitine, pentose, other energymetabolites and optionally at least one vasodilating substance. Ofthese, creatine and magnesium are preferred for combination with ribose.Mammals undergoing high energy demand and loss of fluids also benefitfrom a composition that further comprises electrolytes and an additionalenergy source such as carbohydrate.

BRIEF DESCRIPTION OF THE DRAWINGS

[0021]FIG. 1 shows the dose response of the adenine salvage pathway innormal adult rats to the administration of ribose.

[0022]FIG. 2 shows the mean power output per sprint session of normaladult humans, following administration of ribose or placebo, as measuredon an exercycle.

[0023]FIG. 3 shows the peak power output per sprint session of normaladult humans, following administration of ribose or placebo, as measuredon an exercycle.

DETAILED DESCRIPTION OF THE INVENTION

[0024] The present invention provides a method of stimulating thesynthesis of ATP by the oral administration of a pentose and providespentose-containing compositions that are especially beneficial tomammals undergoing high energy demands or those having chronic lowenergy levels.

[0025] For the purpose of describing this invention, the following termshave the following meanings:

[0026] 1. “Pentose” means a monosaccharide, including but not limitedto, ribose, D-ribose, ribulose, xylitol, xylulose, and any 5-carbonprecursor of ribose.

[0027] 2. “Vasodilator” includes any substance that causes dilation ofblood vessels, including adenine, hydralazine, arginine andnitroglycerine administered transdermally or orally.

[0028] 3. “Intracellular ATP levels” means ATP concentrations measureddirectly by tissue biopsy or nuclear magnetic resonance or indirectly byblood ATP concentration.

[0029] 4. “Other energy metabolites and co-factors” means creatine,co-enzymes, intermediates of the tricarboxylic acid, pentose phosphateor glycolytic enzyme pathways, pyrimidine and purine nucleotides andminerals.

[0030] The compositions preferably contain an energy-enhancing amount ofpentose dissolved or dispersed in an aqueous vehicle such as water, thatmay optionally contain minor but effective amounts of additives such aspolyols, preservatives, flavorings, colorings and the like. Compositionscontaining pentoses adapted for oral administration also include soliddosage forms such as tablets, lozenges, capsules and the like. Pentosesmay also be incorporated in solid nutriments such as bars, moist or drydog food, powders or drink mixes. Effective total dosages of ribose,which can be extrapolated to other pentoses, are disclosed hereinbelow.

[0031] Because pentoses are naturally occurring sugars with a pleasanttaste and virtually no toxicity, subjects may be encouraged toself-administer pentose in the form of tablets, lozenges, powders,suspensions, solutions, or mixed in with solid food. When the subject iscanine or feline, pentose can be easily integrated into “senior diet” or“cardiac diet” and separate administration is not necessary. When thesubject is human, pentose can be included in drinks, bars, shakes orsnack food. The preferred pentose is ribose or xylitol. The preferreddosage is 0.1 to 100 gm pentose per day, preferably 1 to 20 gm pentoseper day. An average adult human may find that 4 to 8 gm pentose per dayis sufficient to provide the benefits of the invention. The upper doseis limited only by the taste preference of the subject, although at veryhigh doses, subjects may experience diarrhea. The dose may be given oncea day in a single unit dosage form, but preferably is given two or threetimes throughout the day, most conveniently during or followingmealtime.

[0032] During strenuous activity, individuals may sweat profusely,requiring replacement of body fluids and electrolytes. Subjects such asdogs, which do not sweat, lose copious amount of water through the lungsand also require fluid replacement. In addition to the advantagesprovided by pentoses alone, with carnitine and or vasodilating agents,it is convenient to include other components within a replacementsolution to be drunk during and following exercise. Rehydrationsolutions such as Gatorade® Thirst Quencher, and Max® drinks are amongthose popular with athletes.

[0033] These sustained energy and anabolic formulas are generally madeup of different carbohydrates, including corn syrup, sucrose, fructose,and maltodextrin; proteins, including casein and other proteins frommilk and soybean; and lipids, including corn, soy, safflower, and canolaoils and medium chain triglycerides. Efforts at improving such“performance drinks” continue.

[0034] U.S. Pat. No. 5,292,538 describes an energy sustainingcomposition containing fructose, glucose, hydrolyzed protein andmagnesium liganded to an amino acid chelate. Other ingredients noted asespecially advantageous include potassium, phosphorus, manganese, zinc,boron, copper, molybdenum, chromium, vanadium, vitamins B_(1,2,5,6) and12, C, E and carnitine.

[0035] U.S. Pat. No. 5,114,723 describes hypotonic beverage compositionsfor oral administration comprising electrolytes, minerals, carbohydratesand other ingredients. The compositions are adjusted to have anosmolarity between 100 and 270 mOs/l.

[0036] Each of these rehydration drinks will be improved by the additionof from about 1 to 20% pentose, most preferably 10% by weight to volume.The amount of pentose to be added will depend on the composition ofother nutrients, to keep the osmolarity within the preferred limits.These drinks will be further improved by the addition of other energymetabolites and co-factors.

The invention will be further described by reference to the followingexamples. EXAMPLE 1. Effect of D-ribose on Nucleotide Salvage in RestingRat Muscle

[0037] It has been theorized but not objectively shown that ribose, viaPRPP synthesis, increases the rate of ATP synthesis via the nucleotidesalvage pathway. However, nothing is known about the total adeninenucleotide (TAN) or ribose levels in the resting muscle and therefore,it is possible that the synthetic enzyme pathway is already saturatedand that administration of ribose does not increase ATP levels innormal, non-ischemic skeletal muscle. In order to demonstrate the effectof ribose on the pathway, plantaris complex muscles of healthy adultmale Sprague-Dawley rats were surgically exposed and perfused withreconstituted blood perfusion medium containing amino acids, mM glucoseand 100 μU of bovine insulin/ml. The muscle was perfused withreconstituted blood medium at ˜40 ml/min, providing tissue perfusion ofapproximately 0.65 ml/min. Varying concentrations of D-ribose were addedto the perfusate to bring the concentration to 0.156 mM, 0.5 mM, 1.58mM, 5.0 mM and 15.0 mM. The muscle was perfused for 30 minutes. Aminimum of two rats was used for analysis at each dose of ribose tested.

[0038] Following perfusion, muscle sections were quickly dissected fromthe limb and freeze-clamped with aluminum tongs chilled in liquidnitrogen. Muscle sections were lyophilized and reconstituted indistilled water for subsequent-separation of adenine nucleotides byreverse-phase high pressure liquid chromatography. Results are expressedas salvage of adenine (i.e., formation of ATP) in nanomoles salvaged pergram wet weight of muscle per hour (nM/gm/hr). TABLE I Ribose SkeletalMuscle Dose-Response Kinetics Saturation Kinetics mM Ribose Observedwith Base 0.000 48.6 0.158 113.0 85.82 0.500 110.0 118.68 1.000 154.121.580 188.5 183.51 2.000 199.74 2.500 215.29 3.000 227.85 5.000 250.0260.68 15.000 315.5 310.37

[0039] As is shown in FIG. 1 and Table I, adenine salvage at zeromillimolar (mM) ribose is less than 50 nM/gm/hr and doubles withadministration of 0.158 mM ribose. At 5 mM ribose, the rate of ATPsynthesis reaches 250 nM/gm/hr. These results show that normal, healthymuscle has low baseline levels of ribose and nucleotide salvagecapability, which can be increased by the administration of ribose.

EXAMPLE 2

[0040] Increased Exercise Capacity in Normal Subjects

[0041] Four healthy, fit subjects in the age range 24 to 26 years of agewere tested. The group was selected to be homogeneous regarding fitnesslevel, gender and mean age with no known metabolic, neuronal, endocrineor cardiopulmonary disorders. All were capable of or had experience withcycling. The study protocol included four phases: (1) an initialbaseline phase consisting of no exercise session; (2) a loading phaseincluding three days of administration of either D-ribose or placebo(glucose) three times per day; (3) a training phase of three daysemploying exercise sessions characterized by serial (N=6) bouts of short(10 second) high-intensity cycle sprints at 7% body mass resistance with50 second rest periods between sprints twice per day (morning andafternoon), and (4) a recovery phase for a period of 48 hours after thefinal training session. FIG. 1 is a diagram of a single cycle sprintbout.

[0042] Muscle biopsies (MB) were performed on the vastis lateralismuscle using both legs in order to evenly distribute and minimizesampling and possible muscle soreness per leg due to the biopsy itself.The first MB was collected at rest at the beginning of the study toestablish a baseline and immediately after the first training-session ofday 0 or the first phase. During the loading phase, no MB was taken.Muscle Biposies were taken following the final training session andafter 48 hours of recovery.

[0043] Two subjects were randomly selected for inclusion into theplacebo or ribose group. Ribose or glucose was administered orally in a250 ml iso-osmotic solution containing 10.0 grams of either ribose orplacebo three times per day for three days preceding training (loadingphase) and for three days during training (training phase). One-halfliter isotonic electrolyte solution was given immediately post exerciseand again 30 minutes later to avoid dehydration.

[0044] The concentration of the following analytes was determined in theMB samples: ATP, ADP, AMP, IMP (inosine monophosphate), TAN (totaladenine nucleotides), creatine phosphate and creatine. TABLE II RiboseAthlete Study Mean Power Per Kilogram (Watts) Subject 1 2 3 4 5 6Average 1P 6.0 6.7 7.3 7.4 7.3 7.5 7.0 2R 6.9 7.5 7.8 7.6 7.9 7.4 7.5 3R8.7 9.2 9.1 9.0 8.5 8.2 8.8 4P 7.5 8.0 7.7 8.7 8.0 7.6 7.9 Placebo 6.87.4 7.5 8.0 7.6 7.5 7.5 100.0% Ribose 7.8 8.4 8.5 8.3 8.2 7.8 8.2 109.0%

[0045] TABLE III Ribose Athlete Study Peak Power Per Kilogram (Watts)Subject 1 2 3 4 5 6 Average 1P 6.8 7.9 8.6 8.6 8.3 9.0 8.2 2R 7.9 8.89.2 9.0 9.4 8.7 8.8 3R 9.8 10.6 10.7 10.7 10.1 9.9 10.3 4P 7.7 8.6 8.79.4 8.8 9.0 8.7 Placebo 7.7 8.6 8.7 9.4 8.8 9.0 8.7 100.0% Ribose 8.99.7 10.0 9.9 9.8 9.3 9.6 109.9%

[0046] TABLE IV Ribose Athlete Study Total Power Per Kilogram Subject 12 3 4 5 6 Average 1P 59.1 67.0 72.7 73.3 72.5 74.2 69.8 2R 71.9 74.777.1 75.6 78.1 73.4 75.1 3R 86.8 91.9 91.3 90.0 85.4 82.5 88.0 4P 74.580.3 76.8 87.4 80.0 76.4 79.2 Placebo 66.8 73.6 74.8 80.4 76.3 75.3 74.5100.0% Ribose 79.3 83.3 84.2 82.8 81.8 77.9 81.6 109.5%

[0047] As can be seen from Tables II to IV and FIGS. 2 and 3,administration of ribose increased performance by 9%.

[0048] The improvement in performance is reflected in the ATP levels inthe muscle biopsies. As shown in Table V, the subjects preloading withribose for three days began the training phase with higher levels ofATP, which declined significantly more than that of the placebo groupafter the sprint bouts, indicating that ATP was being utilized moreefficiently. Recovery of the ribose group at 48 hours was 82% of theinitial level, compared to 78% in the placebo group. TABLE V Mean ATPValues (mmol/kg dw) Recovery Change Change Group Pre Post Recovery % ofPre Pre-Post Post-Rec Placebo 23.60 20.05 18.30 78% −3.55 −1.75 Ribose25.33 13.90 20.80 82% −11.43 6.90

EXAMPLE 3

[0049] Increased Stamina and Feeling of Well-being in Normal, UntrainedSubjects

[0050] D-ribose, given immediately before and during exercise, canprovide a benefit to those subjects who have not been previouslytrained. Four healthy, normal male volunteers will be tested for sprintpower output on an exercycle, as for Example 2 above. Each subject willserve as his own control. Between the sprint bouts, the subjects willcycle slowly and continuously. Total test time will be one hour, withfour sprint bouts during the test. Following the initial baseline testand following each sprint bout, the subjects will be given 5 grams ofD-ribose in 200 ml. of water or a similar tasting placebo (glucose).Sprint power output will be tested 15 minutes after each ingesting ofthe test solutions. Each subject will undergo two sessions, one weekapart, one with ribose and one with placebo, in randomized order. Theplacebo will be sweetened with glucose in order to be indistinguishablefrom the ribose solution. It is expected that the subjects will showhigher power output after ribose administration following sustained mildexercise than they showed after placebo administration. It is furtherexpected that the subjects will have a subjectively higher feeling ofwell being.

EXAMPLE 4

[0051] Relief of Exercise Induced Angina

[0052] A sixty-eight year old male patient with a history of coronaryartery disease, status post triple coronary artery bypass, experiencedexercise induced angina. His present medications are: enalapril (anangiotensin converting enzyme inhibitor), carvedilol (a β blockingagent), nitroglycerine patch and nitroglycerine tablets sublingual asneeded. The most recent coronary angiogram revealed advancement of hiscoronary artery disease with total occlusion of one of the bypassgrafts. The patient performed poorly on two stress tests. His exerciseregimen consisted of a daily walk.

[0053] Due to the development of angina, the patient was able to walkless than one mile per day, at which point he took sublingualnitroglycerine. The patient was given oral D-ribose dissolved in about250 cc. of water. Over a six-month period, the patient receivedintermittent doses of 5-10 grams per day of D-ribose. Post riboseadministration, the patient was able to increase his exercise toleranceto two miles per day without any supplementation of oral nitroglycerine.When the ribose was discontinued, his pre-ribose, anginal-inducingexercise state recurred, which necessitated the use of supplemental oralnitroglycerine. Resumption of oral ribose allowed the patient to walktwo miles per day, without angina or the need for nitroglycerine. Hissubjective evaluation of the ribose treatment is there is “much lessangina pain. I feel better, have more energy and can be more activewithout pain or pills [nitrogycerine].”

EXAMPLE 5

[0054] Improved Treadmill Test Performance

[0055] A sixty-year old male patient with stable coronary artery diseasewas observed to show a greater than fifty percent occlusion of more thanone epicardial coronary artery and stable angina. The patient was testedfor treadmill performance. After two baseline treadmill tests, followingthe Bruce protocol, he received orally administered D-ribose (40 gm inthree divided doses daily) for three days and completed a thirdtreadmill test. At each time, the test was to be stopped when a) thepatient exhibited ST segment depression of 1 mm or more in the ECGtracing; b) when the patient complained of angina or c) when the patientstopped due to dyspnea or fatigue. In each test, this patient concludedthe test due to shortness of breath, but experienced no angina.

[0056] As can be seen from Table VI, the administration of D-ribose forthree days before the final treadmill test increased energy and heartfunction as measured by decrease in rate-pressure product at each stageof testing, including rest (zero time). It is generally accepted thatthe product of heart rate and systemic pressure is a measure ofmyocardial function and energy level, with lower numbers indicatingbetter myocardial function. As a result of the administration of ribose,average tolerated time on the treadmill increased. In addition to theobjective measure of efficacy, the patient subjectively reported feelingmore energetic during ribose administration. TABLE VI Rate-pressureproduct as beats per minute times systolic blood pressure mm Hg TimeBaseline 1 Baseline 2 Average Test % change 0 (rest) 11,088 9,272 10,1809,177 −9.55% 3 minutes 17,574 13,468 15,521 15,272 −1.60% 6 minutes26,500 22,344 24,422 20,592 −15.68% 9 minutes 33,396 29,526 31,46125,356 −9.87% Tolerated 483.00 545.00 514.00 540.00 5.06% time, sec.

EXAMPLE 6

[0057] Self Administration of Ribose

[0058] Patients with chronic illnesses, including but not limited tocoronary artery disease, AIDS, intermittent claudication, tuberculosisand chronic fatigue syndrome, that are characterized by low energylevels, and even those subjects free of overt disease but having lowenergy due to advanced age, trauma, burns, and recovery from illness orsurgery, are benefitted by being able to raise their energy levelswithout continual medical intervention. Many individuals with relativelystable disease live a day to day existence by conforming to an alteredlife style, coupled with pharmaceutical supplementation. Often, suchsubjects are inhibited from undertaking a regimen of moderate physicalactivity from fear of inducing unpleasant effects, such as angina,breathlessness, muscle soreness, cramping or a feeling of exhaustion.Such avoidance lowers the quality of life of the subject and engendersan ever-present background anxiety. In addition, the benefits ofmoderate exercise, which include improved digestion, sleep and a morerelaxed and positive state of mind, are denied to such subjects. Evensubjects free of disease and considered healthy may be dissatisfied withtheir subjective feeling of energy level and well being.

[0059] An example of a subject having no overt disease who benefittedfrom self-administered ribose is a fifty-five year old male. He hadadhered to a strict weekly exercise regimen most of his life untilsustaining a systemic bacterial infection, which required admission tothe intensive care unit for one month and rehabilitation for anadditional month. His cardiovascular and pulmonary systems werepredominantly affected during and following his illness and function hadnot recovered to its previous levels, or to his satisfaction, after oneyear.

[0060] Following convalescence, he has attempted to resume an exerciseregimen, which involves running on a treadmill four days a week andlifting weights for two days a week. The runs were restricted to shortintervals. Following the daily exercises, he has continuouslyexperienced fatigue to the point of exhaustion and has required frequentnaps. The patient began self-administering oral D-ribose at two dosesper day, 4-5 grams per dose. Within seven days, he testified that his“pep” and exercise tolerance increased. For the first time since hisillness, he is able to run as long as 30 minutes on the treadmill. Hestill experiences a Degree of fatigue, but has been able to discontinuethe naps after exercise. He continues on the daily oral doses of ribose,along with his scheduled exercises and feels a continuing improvement inhis energy level after four weeks of ribose administration. He hasexperienced no adverse effects from the ribose.

EXAMPLE 7

[0061] Effect of Ribose with Arginine and/or Carnitine on Subjects withChronic Conditions

[0062] As shown in Example 6, subjects experiencing low energy levelsare predicted to benefit by the self-administration of pentoses. It isfurther predicted that ingestion of a orally acceptable vasodilator suchas L-arginine will have an additional beneficial effect on suchsubjects. It is still further predicted that ingestion of L-carnitine totransport fatty acids into the mitochondria will provide an additionalbeneficial effect to such subjects. It is still further predicted thatthe addition of other energy metabolites and co-factors will provideadditional beneficial effects to such subjects.

[0063] Arginine is known to be a precursor of the endothelium-relaxingfactor nitric oxide. In vitro analyses have determined that under normalcircumstances, an excess of L-arginine is available to endothelialcells. However, in vitro studies have also shown thatendothelium-dependent vasodilatation is improved with the addition ofL-arginine, when L-arginine stores are depleted or if L-glutamine, anantagonist of L-arginine, is present. It was not known, prior to thisinvention, if oral arginine can enhance cardiac perfusion and thus thedistribution of ribose to muscle tissue. The test group chosen will behuman patients with low energy levels due to cardiac disease, which isan available and well-studied group. The results are expected to applyequally to other subjects having low energy levels, such as subjectswith debilitating diseases and elderly human and canines.

[0064] Thirty adult (45-70 years of age) subjects with known stablecoronary artery disease, but without resting ischemia, will berandomized into three separate groups. Each patient will be subjected toa serial exercise treadmill testing to initially qualify for admissioninto this protocol. A final treadmill test will be performed after athree day course of either L-arginine, D-ribose, L-carnitine or acombination of L-arginine, D-ribose and L-carnitine. The end points ofthis study will investigate-time to development of angina pectorisand/or electrocardiographic changes during treadmill exercise.

[0065] It is expected that these test subjects will show even moreimprovement than the 10% decrease in rate-pressure and 5% increase intolerated time as shown in Example 2.

[0066] All publications and patents cited herein are incorporated byreference as though fully set forth. This invention has been describedwith respect to various specific and preferred embodiments. However, itshould be understood that many variations or modifications may be madewhile remaining within the spirit and scope of the invention.

We claim:
 1. A method for increasing the energy levels of a mammal whichcomprises the oral administration of an effective amount of a pentose tosaid mammal.
 2. The method according to claim 1 wherein the pentose isribose.
 3. The method according to claim 1 wherein the mammal hasreduced availability of ATP.
 4. The method according to claim 1 whereinthe mammal has increased energy demand.
 5. The method according to claim3 wherein the mammal has coronary artery disease.
 6. The methodaccording to claim 4 wherein the mammal is recovering from infection,trauma or bum.
 7. The method according to claim 4 wherein the mammal isexercising strenuously.
 8. The method according to claim 4 wherein themammal has not been subjected to ischemic insult.
 9. A composition to beadministered to increase energy levels in mammals which comprises aneffective amount of a pentose.
 10. A composition according to claim 9wherein the pentose is ribose.
 11. A composition according to claim 9which further comprises magnesium, and creatine.
 12. A unit dosage formcomprising about 0.1 to 50 gm pentose in combination with apharmaceutically acceptable vehicle, adapted for oral ingestion.
 13. Theunit dosage form of claim 12, wherein the pentose is ribose.
 14. Theunit dosage form of claim 12 wherein the vehicle is a liquid.
 15. Theunit dosage form of claim 14 wherein the liquid is an aqueous liquid.16. The unit dosage form of claim 12 wherein the vehicle is a solid orsemi-solid edible vehicle.